Linda Garrard

Increasing benefit from revascularization is associated with increasing amounts of myocardial hibernation: a substudy of the PARR-2 trial.

OBJECTIVES We sought to determine: 1) whether F-18-fluorodeoxyglucose (FDG) positron emission tomography (PET) parameters identify high-risk patients who gain benefit from revascularization; 2) whether there is a cut point for such benefit; and 3) predictors of outcome in patients with severe left ventricular (LV) dysfunction due to coronary artery disease. BACKGROUND Patients with ischemic LV dysfunction might benefit from revascularization but not without risk. The FDG PET imaging can detect viable myocardium that recovers after revascularization. In the PARR-2 (PET and Recovery Following Revascularization-2) trial, FDG PET imaging showed a nonsignificant trend for improved outcome compared with standard care. Understanding the predictors of outcome from this prospective trial should help better identify patients at risk and which patients most benefit from revascularization. METHODS This post hoc analysis included 182 patients with left ventricular ejection fraction (LVEF) <35% and coronary artery disease, being considered for revascularization work-up, and randomized to the PET arm of PARR-2. The primary outcome was a composite of cardiac death, myocardial infarction, or cardiac repeat hospital stay at 1 year. RESULTS There is an interaction between PET mismatch and protocol revascularization such that higher mismatch, when combined with revascularization, yields fewer primary outcome events (p = 0.02). On the basis of adjusted Cox modeling, with reduced mismatch (<7%), the risk is not significantly different with or without revascularization. As mismatch increases above this mark, risk is reduced with revascularization. Increasing creatinine (for a 10-mumol/l increase: hazard ratio: 1.03, 95% confidence interval: 1.01 to 1.06, p = 0.010) is also associated with increased risk, whereas decreasing LVEF (for a 2% decrease: hazard ratio: 1.08, 95% confidence interval: 0.99 to 1.18, p = 0.087) trends toward an association with increased risk. CONCLUSIONS In this post hoc analysis, patients with ischemic cardiomyopathy with larger amounts of mismatch have improved outcome with revascularization. Renal function was also an independent predictor of outcome. The FDG PET seems to define high-risk patients that gain benefit from revascularization. (PET and Recovery Following Revascularization [PARR 2]; NCT00385242).

18F-FDG PET Imaging of Myocardial Viability in an Experienced Center with Access to 18F-FDG and Integration with Clinical Management Teams: The Ottawa-FIVE Substudy of the PARR 2 Trial

18F-FDG PET may assist decision making in ischemic cardiomyopathy. The PET and Recovery Following Revascularization (PARR 2) trial demonstrated a trend toward beneficial outcomes with PET-assisted management. The substudy of PARR 2 that we call Ottawa-FIVE, described here, was a post hoc analysis to determine the benefit of PET in a center with experience, ready access to 18F-FDG, and integration with clinical teams. Methods: Included were patients with left ventricular dysfunction and suspected coronary artery disease being considered for revascularization. The patients had been randomized in PARR 2 to PET-assisted management (group 1) or standard care (group 2) and had been enrolled in Ottawa after August 1, 2002 (the date that on-site 18F-FDG was initiated) (n = 111). The primary outcome was the composite endpoint of cardiac death, myocardial infarction, or cardiac rehospitalization within 1 y. Data were compared with the rest of PARR 2 (PET-assisted management [group 3] or standard care [group 4]). Results: In the Ottawa-FIVE subgroup of PARR 2, the cumulative proportion of patients experiencing the composite event was 19% (group 1), versus 41% (group 2). Multivariable Cox proportional hazards regression showed a benefit for the PET-assisted strategy (hazard ratio, 0.34; 95% confidence interval, 0.16–0.72; P = 0.005). Compared with other patients in PARR 2, Ottawa-FIVE patients had a lower ejection fraction (25% ± 7% vs. 27% ± 8%, P = 0.04), were more often female (24% vs. 13%, P = 0.006), tended to be older (64 ± 10 y vs. 62 ± 10 y, P = 0.07), and had less previous coronary artery bypass grafting (13% vs. 21%, P = 0.07). For patients in the rest of PARR 2, there was no significant difference in events between groups 3 and 4. The observed effect of 18F-FDG PET–assisted management in the 4 groups in the context of adjusted survival curves demonstrated a significant interaction (P = 0.016). Comparisons of the 2 arms in Ottawa-FIVE to the 2 arms in the rest of PARR 2 demonstrated a trend toward significance (standard care, P = 0.145; PET-assisted management, P = 0.057). Conclusion: In this post hoc group analysis, a significant reduction in cardiac events was observed in patients with 18F-FDG PET–assisted management, compared with patients who received standard care. The results suggest that outcome may be benefited using 18F-FDG PET in an experienced center with ready access to 18F-FDG and integration with imaging, heart failure, and revascularization teams.

Effects of Short-Term Continuous Positive Airway Pressure on Myocardial Sympathetic Nerve Function and Energetics in Patients With Heart Failure and Obstructive Sleep Apnea A Randomized Study

Background— Heart failure with reduced ejection fraction and obstructive sleep apnea (OSA), 2 states of increased metabolic demand and sympathetic nervous system activation, often coexist. Continuous positive airway pressure (CPAP), which alleviates OSA, can improve ventricular function. It is unknown whether this is due to altered oxidative metabolism or presynaptic sympathetic nerve function. We hypothesized that short-term (6–8 weeks) CPAP in patients with OSA and heart failure with reduced ejection fraction would improve myocardial sympathetic nerve function and energetics. Methods and Results— Forty-five patients with OSA and heart failure with reduced ejection fraction (left ventricular ejection fraction 35.8±9.7% [mean±SD]) were evaluated with the use of echocardiography and 11C-acetate and 11C-hydroxyephedrine positron emission tomography before and ≈6 to 8 weeks after randomization to receive short-term CPAP (n=22) or no CPAP (n=23). Work metabolic index, an estimate of myocardial efficiency, was calculated as follows: (stroke volume index×heart rate×systolic blood pressure÷Kmono), where Kmono is the monoexponential function fit to the myocardial 11C-acetate time-activity data, reflecting oxidative metabolism. Presynaptic sympathetic nerve function was measured with the use of the 11C-hydroxyephedrine retention index. CPAP significantly increased hydroxyephedrine retention versus no CPAP (&Dgr;retention: +0.012 [0.002, 0.021] versus −0.006 [−0.013, 0.005] min−1; P=0.003). There was no significant change in work metabolic index between groups. However, in those with more severe OSA (apnea-hypopnea index >20 events per hour), CPAP significantly increased both work metabolic index and systolic blood pressure (P<0.05). Conclusions— In patients with heart failure with reduced ejection fraction and OSA, short-term CPAP increased hydroxyephedrine retention, indicating improved myocardial sympathetic nerve function, but overall did not affect energetics. In those with more severe OSA, CPAP may improve cardiac efficiency. Further outcome-based investigation of the consequences of CPAP is warranted. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00756366.

Alternative Imaging Modalities in Ischemic Heart Failure (AIMI-HF) IMAGE HF Project I-A: study protocol for a randomized controlled trial

BackgroundIschemic heart disease (IHD) is the most common cause of heart failure (HF); however, the role of revascularization in these patients is still unclear. Consensus on proper use of cardiac imaging to help determine which candidates should be considered for revascularization has been hindered by the absence of clinical studies that objectively and prospectively compare the prognostic information of each test obtained using both standard and advanced imaging.Methods/DesignThis paper describes the design and methods to be used in the Alternative Imaging Modalities in Ischemic Heart Failure (AIMI-HF) multi-center trial. The primary objective is to compare the effect of HF imaging strategies on the composite clinical endpoint of cardiac death, myocardial infarction (MI), cardiac arrest and re-hospitalization for cardiac causes.In AIMI-HF, patients with HF of ischemic etiology (n = 1,261) will follow HF imaging strategy algorithms according to the question(s) asked by the physicians (for example, Is there ischemia and/or viability?), in agreement with local practices. Patients will be randomized to either standard (SPECT, Single photon emission computed tomography) imaging modalities for ischemia and/or viability or advanced imaging modalities: cardiac magnetic resonance imaging (CMR) or positron emission tomography (PET). In addition, eligible and consenting patients who could not be randomized, but were allocated to standard or advanced imaging based on clinical decisions, will be included in a registry.DiscussionAIMI-HF will be the largest randomized trial evaluating the role of standard and advanced imaging modalities in the management of ischemic cardiomyopathy and heart failure. This trial will complement the results of the Surgical Treatment for Ischemic Heart Failure (STICH) viability substudy and the PET and Recovery Following Revascularization (PARR-2) trial. The results will provide policy makers with data to support (or not) further investment in and wider dissemination of alternative ‘advanced’ imaging technologies.Trial registrationNCT01288560

Long-Term Follow-Up of Outcomes With F-18-Fluorodeoxyglucose Positron Emission Tomography Imaging–Assisted Management of Patients With Severe Left Ventricular Dysfunction Secondary to Coronary Disease

Background—Whether viability imaging can impact long-term patient outcomes is uncertain. The PARR-2 study (Positron Emission Tomography and Recovery Following Revascularization) showed a nonsignificant trend toward improved outcomes at 1 year using an F-18-fluorodeoxyglucose positron emission tomography (PET)–assisted strategy in patients with suspected ischemic cardiomyopathy. When patients adhered to F-18-fluorodeoxyglucose PET recommendations, outcome benefit was observed. Long-term outcomes of viability imaging–assisted management have not previously been evaluated in a randomized controlled trial. Methods and Results—PARR-2 randomized patients with severe left ventricular dysfunction and suspected CAD being considered for revascularization or transplantation to standard care (n= 195) versus PET-assisted management (n=197) at sites participating in long-term follow-up. The predefined primary outcome was time to composite event (cardiac death, myocardial infarction, or cardiac hospitalization). After 5 years, 105 (53%) patients in the PET arm and 111 (57%) in the standard care arm experienced the composite event (hazard ratio for time to composite event =0.82 [95% confidence interval 0.62–1.07]; P=0.15). When only patients who adhered to PET recommendations were included, the hazard ratio for the time to primary outcome was 0.73 (95% confidence interval 0.54–0.99; P=0.042). Conclusions—After a 5-year follow-up in patients with left ventricular dysfunction and suspected CAD, overall, PET-assisted management did not significantly reduce cardiac events compared with standard care. However, significant benefits were observed when there was adherence to PET recommendations. PET viability imaging may be best applied when there is likely to be adherence to imaging-based recommendations. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00385242.

In Vivo Assessment of Myocardial Glucose Uptake by Positron Emission Tomography in Adults With the PRKAG2 Cardiac Syndrome

Background—The PRKAG2 cardiac syndrome is an inherited metabolic disease of the heart characterized by excessive myocardial glycogen deposition. The biochemical alterations associated with this condition remain controversial and have not previously been studied in affected humans. Methods and Results—Positron emission tomography (PET) imaging was used to quantitatively assess myocardial glucose uptake (MGU) in 6 adult subjects with the PRKAG2 cardiac syndrome and 6 healthy, matched control subjects using the glucose analogue 18F-Fluoro-2-deoxyglucose (FDG). Studies were performed under a euglycemic hyperinsulinemic clamp to ensure stable blood glucose levels. Rubidium-82 perfusion scans were performed to ensure that myocardial differences in myocardial glucose uptake were not the result of significant myocardial scar. In adult patients with phenotypic expression of disease, the median myocardial glucose uptake of the left ventricle was 0.18 &mgr;mol/min/g (interquartile range, 0.14, 0.24), compared with 0.40 &mgr;mol/min/g (interquartile range, 0.30 to 0.45) in the control group (P=0.01). The median blood glucose during FDG-PET imaging was 4.72 mmol/L (interquartile range, 4.32 to 4.97) in the PRKAG2 group and 4.38 mmol/L (interquartile range, 3.90, 4.79) in the control group (P=NS). The significant decrease observed in myocardial glucose uptake in affected patients occurred in the absence of significant myocardial scar. Conclusions—The PRKAG2 cardiac syndrome is associated with a reduction of glucose uptake in adult patients affected with this genetic condition. In this pilot study, 18F-FDG-PET imaging is a useful tool to assess alterations in myocardial glucose transport in this inherited metabolic disease and provide insight into the biochemical pathophysiology of the diseased state.

Does FDG PET-Assisted Management of Patients With Left Ventricular Dysfunction Improve Quality of Life? A Substudy of the PARR-2 Trial

BACKGROUND Patients with left ventricular dysfunction whose management is directed by F-18-fluorodeoxyglucose (FDG) positron emission tomography (PET) imaging may have a quality of life (QOL) benefit over standard care. METHODS Among 430 patients randomized in the PET and Recovery Following Revascularization (PARR)-2 trial to FDG PET-assisted management vs standard, QOL scores were obtained using the European Quality of Life-5 Dimensions (EQ-5D) in 427 patients at baseline (FDG PET n = 216; standard n = 211) and 355 patients at 12-month follow-up (FDG PET n = 184; standard n = 171). EQ-5D scores between FDG PET and standard arms were compared using mixed model repeated measures (MMRM). Subgroup analysis compared EQ-5D scores between patients in FDG PET who adhered to PET recommendations (Adherence) vs standard using MMRM. Interaction of revascularization with management was assessed using a general linear model. RESULTS A trend toward higher EQ-5D scores in FDG PET was observed (P = 0.056). Subgroup analysis showed a significant difference favouring adherence (P = 0.04). Higher QOL at 6 months for FDG PET (P = 0.02) and Adherence (P = 0.02) were observed. For revascularization, an interaction with management (FDG PET vs standard) for QOL was observed (6 months: P = 0.01; 12 months: P = 0.1); Adherence (6 months: P = 0.01; 12 months: P = 0.1). CONCLUSIONS FDG PET-directed management improves QOL, at least in the short-term and with adherence to recommendations. This may relate to revascularization, and may indicate better treatment selection using FDG PET.

[18F]-Fluorodeoxyglucose PET/CT imaging as a marker of carotid plaque inflammation: Comparison to immunohistology and relationship to acuity of events

BACKGROUND [18F]-fluorodeoxyglucose (18FDG) uptake imaged with positron emission tomography (PET) and computed tomography (CT) may serve as a biomarker of plaque inflammation. This study evaluated the relationship between carotid plaque 18FDG uptake and a) intraplaque expression of macrophage and macrophage-like cellular CD68 immunohistology; b) intraplaque inflammatory burden using leukocyte-sensitive CD45 immunohistology; c) symptomatic patient presentation; d) time from last cerebrovascular event. METHODS 54 patients scheduled for carotid endarterectomy underwent 18FDG PET/CT imaging. Maximum 18FDG uptake (SUVmax) and tissue-to-blood ratio (TBRmax) was measured for carotid plaques. Quantitative immunohistological analysis of macrophage-like cell expression (CD68) and leukocyte content (CD45) was performed. RESULTS 18FDG uptake was related to CD68 macrophage expression (TBRmax: r = 0.51, p < 0.001), and total-plaque leukocyte CD45 expression (TBRmax: r = 0.632, p = 0.009, p < 0.001). 18FDG TBRmax uptake in carotid plaque associated with patient symptoms was greater than asymptomatic plaque (3.58 ± 1.01 vs. 3.13 ± 1.10, p = 0.008). 18FDG uptake differed between an acuity threshold of <90 days and >90 days (SUVmax:3.15 ± 0.87 vs. 2.52 ± 0.45, p = 0.015). CONCLUSIONS In this CAIN cohort, 18FDG uptake imaged with PET/CT serves a surrogate marker of intraplaque inflammatory macrophage, macrophage-like cell and leukocyte burden. 18FDG uptake is greater in plaque associated with patient symptoms and those with recent cerebrovascular events. Future studies are needed to relate 18FDG uptake and disease progression.

Computed tomographic coronary angiography for patients with heart failure (CTA-HF): a randomized controlled trial (IMAGE HF Project 1-C)

AbstractBackgroundThe prevalence of heart failure (HF) is rising in industrialized and developing countries. Though invasive coronary angiography (ICA) remains the gold standard for anatomical assessment of coronary artery disease in HF patients, alternatives are being sought. Computed tomographic coronary angiography (CTA) has emerged as an accurate non-invasive diagnostic tool for coronary artery disease (CAD) and has been demonstrated to have prognostic value. Whether or not CTA can be used in HF patients is unknown. Acknowledging the aging population, the growing prevalence of HF and the increasing financial burden of healthcare, we need to identify non-invasive diagnostic tests that are available, safe, accurate and cost-effective.Methods/DesignThe proposed study aims to provide insight into the efficacy of CTA in HF patients. A multicenter randomized controlled trial will enroll 250 HF patients requiring coronary anatomical definition. Enrolled patients will be randomized to either CTA or ICA (n = 125 per group) as the first test to define coronary anatomy. The primary outcomes will be collected to determine downstream resource utilization. Secondary outcomes will include the composite clinical events and major adverse cardiac events. In addition, the accuracy of CTA for detecting coronary anatomy and obstruction will be assessed in patients who subsequently undergo both CTA and ICA. It is expected that CTA will be a more cost-effective strategy for diagnosis: yielding similar outcomes with fewer procedural risks and improved resource utilization.Trial registrationClinicalTrials.gov,NCT01283659 Team grant #CIF 99470

Identification of Inflamed Aortic Plaque in Conventional Fluorodeoxyglucose–Positron Emission Tomography Myocardial Viability Studies

BACKGROUND It has been shown that (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET) is useful in identifying inflamed plaque in major arteries. This study evaluated the feasibility of inflamed plaque detection with routinely acquired cardiac FDG-PET viability studies in patients with severe coronary artery disease and left ventricular dysfunction. METHODS Clinically indicated myocardial viability scans using FDG and PET combined with computed tomography from 103 patients were retrospectively analyzed for FDG uptake in the proximal, ascending, and descending thoracic aorta. Aortic uptake was graded on the basis of peak and mean target-to-background ratio (TBR): grade 0, < 1; grade 1, 1.01-1.49; grade 2, 1.5-1.99; and grade 3, > 2. RESULTS Of the 103 patients, 71 (68.9%) had a history of myocardial infarction, 88 (85.4%) were on statins, and 70 (68%) were on angiotensin-converting enzyme (ACE) inhibitors. Increased FDG uptake (mean TBR grade 1-3) was seen in 79 of 103 patients (77%), and grade 3 aortic uptake based on peak TBR was found in 12 of 103 patients (12%). CONCLUSIONS Detection of inflamed atherosclerotic plaque in the aorta with conventional FDG viability scans is feasible. The rate of very positive uptake in this population of ischemic heart disease patients is low, possibly reflecting aggressive secondary risk factor modification including statin and ACE inhibitor use.